warfarin and nefazodone

Hydroxymethyl glutaryl-CoA (HMG-CoA) reductase inhibitors (Statins) are used to treat dyslipidemia. Generally, the statins are the substrates of CYP enzymes, P-glycoprotein (P-gp), and organic anion transporting polypeptides transporters (OATP1B1).. This review article focuses on the clinical significance of statins, and their interactions in real practice.. The databases like Medline/PubMed Central/PubMed, Google Scholar, Science Direct, Cochrane Library, Directory of open access journals (DOAJ), and reference lists were searched to identify relevant articles.. Most of the drug interactions of statins result in elevated plasma concentrations and toxicity of statins due to the inhibition of CYP3A4, P-gp and/or OATP1B1 transporters. The toxicity of statins includes myopathy, rhabdomyolysis, elevated liver enzymes, acute kidney injury, and diabetes. The statins like simvastatin, lovastatin, and atorvastatin are substrates of CYP3A4 enzyme and P-glycoprotein and their concomitant use with the drugs inhibiting or inducing them would result in changes in plasma concentrations and toxicity/efficacy. However, the statins like pravastatin, rosuvastatin and pitavastatin are not substrates of CYP enzymes and hence the concomitant use of CYP inhibitors or inducers does not affect them. Almost all the statins are the substrates of OATP1B1 transporter, and the co-prescription of inhibitors of OATP1B1 elevates the plasma concentrations and muscle toxicity of statins.. Understanding the interacting potential of each statin will enable the prescribers, pharmacists, and other health care professionals to use statins effectively without compromising patient safety.

Topics: Anti-Infective Agents; Anticonvulsants; Antiviral Agents; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cardiovascular Agents; Colchicine; Contraceptives, Oral; Cytochrome P-450 CYP3A; Drug Interactions; Fibric Acids; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Immunosuppressive Agents; Organic Anion Transporters; Phosphodiesterase 5 Inhibitors; Piperazines; Triazoles; Warfarin

Nefazodone, an antidepressant with serotonin and norepinephrine receptor modulating activity, is highly protein bound and eliminated by oxidative metabolism. This study evaluated the potential for clinically significant drug interactions with warfarin and nefazodone coadministration. Eighteen subjects received warfarin daily for 14 days, achieving steady-state warfarin concentrations and a stable prothrombin ratio. Nefazodone 200 mg every 12 hours (n = 12) or placebo every 12 hours (n = 6) was then added to the daily warfarin dose for the next 7 days in a double-blind, randomized design. No serious or unexpected adverse events or events suggestive of abnormal bleeding occurred during coadministration. The addition of nefazodone had no effect on the unbound fraction of total warfarin in plasma or on the steady-state pharmacokinetics of R-warfarin based on within-subject or comparison to placebo-treated subjects. The steady-state AUCTAU over the dosing interval and Cmax of S-warfarin decreased by 12%; however, this change is clinically insignificant because the prothrombin ratio and bleeding time remained unchanged. The steady-state minimum concentrations for nefazodone and metabolites, achieved on coadministration day 3, were typical of healthy men treated with this nefazodone dosage. In conclusion, warfarin and nefazodone coadministration was safe and well-tolerated with no clinically significant interactions.

Topics: Adult; Anticoagulants; Antidepressive Agents; Double-Blind Method; Drug Administration Schedule; Drug Interactions; Humans; Male; Piperazines; Tablets; Triazoles; Warfarin